Human immunodeficiency virus (HIV) has infected over 34 million people worldwide and this infection leads to immune suppression with selective depletion of CD4 + T cells. This decrease in immune function leads to numerous oppommistic infections with over 50% of HIV-infected individuals developing pathology involving the oral cavity. Among the pathogens responsible for oral disease is the mucosatropic human Papilloma virus (HPV), which is the most common viral sexually transmitted disease and the etiologic agent of mucosal warts and anogenital malignancies. HPV associated oral lesions include condyloma, focal epithelial hyperplasia and some squamous cell carcinomas. Both oral and genital lesions caused by HPV are more commonly seen in those co-infected with HIV. Systemic immune reconstitution for the HIV + patient has been accomplished with highly active anti-retroviral therapy (HAART) leading to decreases in mortality, morbidity as well as systemic and oral opportunistic infections, including regression of HPV-induced cervical lesions. Paradoxically, recent reports have noticed increases in oral pathology consistent with HPV infection in the presence of HAART. If this observation can be confirmed, it suggests that the host defense against oral HPV infection is independent of that restored by HAART and may be adversely affected. Unfortunately, little is known about the natural history of HPV infection in the HIV-positive patient or the local immune dysfunction allowing the development of HPV oral lesions. We hypothesize that oral HPV infection and disease results from decreased oral-based immunity in the HIV co-infected individual that cannot be restored and is potentially reduced further by HAART. To begin to test this hypothesis, we will investigate the impact of effective HAART therapy on the progression of HPV infection and also the salivary immune response to the virus, followed by the characterization of the local immune response in those that develop HPV-related oral lesions. Results from this study will be evaluated for possible immunotherapeutic potential in the treatment of oral HPV infections.